Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions.

Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function, and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs), and Plexin D1 located at cell-cell junctions mediates many of these events. However, available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial-specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encoding Adgrl2 gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology, and disease.

Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis.

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.

Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in Hsd17b13 knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the HSD17B13 rs72613567-A variant in humans and by the Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the HSD17B13-induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.

Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.

AIMS/HYPOTHESIS: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content. METHODS: C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle. RESULTS: We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine1150 on the insulin receptor kinase (IRKT1150), and reductions in insulin-stimulated IRKY1162 phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively. CONCLUSIONS/INTERPRETATION: These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice.

The Prophylaxis Effect of Ephedrine on Hemodynamic Variation in Patients Undergoing Percutaneous Nephrolithotomy Surgery with Spinal Anesthesia.

Background: Performing spinal anesthesia with at least hemodynamic variation and complications is always challenging for anesthesiologists. In this study, we investigated the effect of ephedrine and placebo on hemodynamic changes in patients undergoing percutaneous nephrolithotomy with spinal anesthesia. Methods: This randomized, double-blind prospective clinical trial was conducted on 120 patients aged 20‒60 years with ASA (American Society of Anesthesiologists) classes I and II. Patients who were candidates for percutaneous nephrolithotomy with spinal anesthesia were divided into intervention (received 1 cc = 5 mg ephedrine) and control groups (received 1 cc normal saline). All vital parameters, including HR (heart rate) and NIBP (noninvasive blood pressure), were recorded perioperatively T0-T25) and finally at the end of surgery time (Tf). The results were analyzed by SPSS software version 23, and a P value ≤0.05 was considered significant. Results: The mean arterial pressure during surgery between T3 and T9 and the mean heart rate in times of T3-T8 in the intervention group were higher than in the control group, and this difference was statistically significant (P < 0.05). The incidence of hypotension, bradycardia, nausea, and vomiting and the amount of prescribed ephedrine, atropine, and ondansetron in the control group were higher than in the intervention group (P=0.001). Seven patients in the control group and four in the intervention group had shivering, but this difference was not statistically significant (P=0.43). Conclusion: This study showed the effectiveness of the prescription of 5 mg ephedrine two minutes before changing from the lithotomy position to the supine in maintaining hemodynamic stability, reducing hypotension, bradycardia, nausea, and vomiting, and the amount of prescribed ephedrine, atropine, and ondansetron. Trial Registrations. This trial is registered with IRCT20160430027677N22.

Leadership in limbo: Characteristics of successful incident commanders in health sector of a disaster-prone country.

OBJECTIVE: Iran, as one of the most disaster-prone countries in the world, is exposed to a wide range of hazards. Hence, the health sector should be prepared to deal with the consequences of emergencies. This study aimed to explore Iranian disaster management status and to identify the necessary characteristics of successful incident commanders in this field. METHODS: A qualitative content analysis was designed using in-depth semi-structured interviews with 30 commanders and experts, selected by purposeful sampling, who had first-hand experiences in managing health disasters. Field notes, formal institutional reports, and photos were employed as well. Verbatim transcribed interviews and other data sources were analyzed using constant comparison method. Ethical issues were considered carefully throughout the study process. RESULTS: Two main themes were developed: The first theme, "limbo situation," as expression of the problem describes inadequacies and complexities of disaster management in Iranian health sector, including seven categories. The second theme was "effective disaster leadership" consisting of "commanders' traits" and "commanders' competencies" as subthemes. CONCLUSIONS: The study demonstrated the chaotic feature of disaster management in Iran and probably some other developing countries, with crucial and unclear role of field commanders. Working under stress, time pressure, uncertainty, and management of paradoxes needs timely and on-field decision making. This study revealed that Iranian health sector incident commanders should be transformational leaders with the ability of influencing subordinate staff and have Janusian thinking skills for overcoming the existing limbo situation.

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents.

AIMS/HYPOTHESIS: Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake. METHODS: ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. RESULTS: Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. CONCLUSIONS/INTERPRETATION: Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.

Comparison of serum levels of IL-6, IL-8, TGF-ß and TNF-α in coronary artery diseases, stable angina and participants with normal coronary artery.

Cytokines, which typically regulate the immune responses, play a role in cardiovascular diseases such as coronary artery diseases (CAD) and ischemic heart diseases (IHD). The aims of this study were to evaluate serum levels of IL-6, IL-8, TGF-ß and TNF-α in patients with or without CAD, as well as stable angina, and to assess the effects of drug administration on the serum levels of these cytokines. Serum levels of the cytokines were analyzed in the three groups: patients with acute coronary syndrome, stable angina and participants with normal coronary arteries as controls. Cohort study of the patients showed that Nitrocontin was the only drug used in a significantly different pattern between the groups where it was used less frequently in patients with stable angina compared to the acute coronary syndrome or control groups. Serum levels of the evaluated cytokines were not different neither between the studied groups nor between the groups with variable Gensini scores. However, IL-8 in controls that were not engaged in regular exercise was higher than the controls performing regular exercise. In the stable angina group, TNF-α in non-smokers was higher than the smokers. It was revealed that serum levels of pro-inflammatory cytokines are not associated with atherosclerosis and stable angina in patients from the South-East of Iran. However, suppressed expression of TGF-ß, may increase the risk of CAD. Exercise can reduce the risk of CAD through downregulation of pro-inflammatory cytokines.

Naltrexone; as an efficient adjuvant in induction of Th1 immunity and protection against Fasciola hepatica infection.

Toxic effects of available therapeutics are major drawbacks for conventional management approaches in parasitic infections. Vaccines have provided a promising opportunity to obviate such unwanted complications. In present study, we examined immune augmenting capacities of an emerging adjuvant, Naltrexone, against Fasciola hepatica infection in BALB/c mice. Seventy BALB/c mice were divided into five experimental groups (14 mice per group) including 1- control (received PBS), 2- vaccine (immunized with F. hepatica E/S antigens), 3- Alum-vaccine (immunized with Alum adjuvant and E/S antigens), 4- NLT-vaccine (immunized with NLT adjuvant and E/S antigens), and 5- Alum-NLT-vaccine (immunized with mixed Alum-NLT adjuvant and E/S antigens). Lymphocyte stimulation index was assessed by MTT assay. Production of IFN-γ, IL-4, IgG2a and IgG1 was assessed by ELISA method. Results showed that NLT, either alone or in combination with alum, can induce immune response toward production of IFN-γ and IgG2a as representatives of Th1 immune response. Also, using this adjuvant in immunization experiment was associated with significantly high proliferative response of splenocytes/lymphocytes. Utilization of mixed Alum-NLT adjuvant revealed the highest protection rate (73.8%) in challenge test of mice infected with F. hepatica. These findings suggest the potential role of NLT as an effective adjuvant in induction of protective cellular and Th1 immune responses against fasciolosis.

Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice.

Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. PARK2 is a ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of PARK2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed a high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after 1-wk HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of PARK2 during metabolic stress.

Toll-like receptor 2 and type 2 diabetes.

Innate immunity plays a crucial role in the pathogenesis of type 2 diabetes and related complications. Since the toll-like receptors (TLRs) are central to innate immunity, it appears that they are important participants in the development and pathogenesis of the disease. Previous investigations demonstrated that TLR2 homodimers and TLR2 heterodimers with TLR1 or TLR6 activate innate immunity upon recognition of damage-associated molecular patterns (DAMPs). Several DAMPs are released during type 2 diabetes, so it may be hypothesized that TLR2 is significantly involved in its progression. Here, we review recent data on the important roles and status of TLR2 in type 2 diabetes and related complications.

The remarkable migration of the medial collateral ligament.

The developing cortical surfaces of long bones are sculpted and modeled by periosteal osteoclasts and osteoblasts. These surfaces also receive the insertions of tendons and ligaments, and these insertion sites too are modeled to form the root systems that anchor them into the cortical bone. The regulatory molecules that control modeling are poorly understood, but recent evidence suggests that parathyroid hormone-related protein (PTHrP) participates in this process. PTHrP functions principally as a paracrine regulatory molecule, and is known to be induced by mechanical loading in a number of sites. The most curious example of developmental modeling of the cortex is the migration of insertion sites such as that of the medial collateral ligament (MCL) along the bone surface during long-bone growth. We report here the mechanisms that mediate MCL migration using a combination of genetic, imaging and histological techniques. We describe a MCL migratory complex that comprises two components. The first is the MCL insertion site itself, which is a prototypical fibrous insertion site with coupled osteoclast and osteoblast activities, and its key feature is that it is anchored early in development, well before initiation of the long-bone growth spurt. Above the insertion site the periosteum is excavated by osteoclasts to form a migratory tract; this is mediated by wholly uncoupled osteoclastic bone resorption and remains as an unmineralized canal on the cortical surface in the adult. Load-induction of PTHrP appears to regulate the osteoclastic activity in both the insertion site and migratory tract.

Periosteal PTHrP regulates cortical bone modeling during linear growth in mice.

The modeling of long bone surfaces during linear growth is a key developmental process, but its regulation is poorly understood. We report here that parathyroid hormone-related peptide (PTHrP) expressed in the fibrous layer of the periosteum (PO) drives the osteoclastic (OC) resorption that models the metaphyseal-diaphyseal junction (MDJ) in the proximal tibia and fibula during linear growth. PTHrP was conditionally deleted (cKO) in the PO via Scleraxis gene targeting (Scx-Cre). In the lateral tibia, cKO of PTHrP led to a failure of modeling, such that the normal concave MDJ was replaced by a mound-like deformity. This was accompanied by a failure to induce receptor activator of NF-kB ligand (RANKL) and a 75% reduction in OC number (P ≤ 0.001) on the cortical surface. The MDJ also displayed a curious threefold increase in endocortical osteoblast mineral apposition rate (P ≤ 0.001) and a thickened cortex, suggesting some form of coupling of endocortical bone formation to events on the PO surface. Because it fuses distally, the fibula is modeled only proximally and does so at an extraordinary rate, with an anteromedial cortex in CD-1 mice that was so moth-eaten that a clear PO surface could not be identified. The cKO fibula displayed a remarkable phenotype, with a misshapen club-like metaphysis and an enlargement in the 3D size of the entire bone, manifest as a 40-45% increase in the PO circumference at the MDJ (P ≤ 0.001) as well as the mid-diaphysis (P ≤ 0.001). These tibial and fibular phenotypes were reproduced in a Scx-Cre-driven RANKL cKO mouse. We conclude that PTHrP in the fibrous PO mediates the modeling of the MDJ of long bones during linear growth, and that in a highly susceptible system such as the fibula this surface modeling defines the size and shape of the entire bone.

Investigation the efficacy of intra-articular prolotherapy with erythropoietin and dextrose and intra-articular pulsed radiofrequency on pain level reduction and range of motion improvement in primary osteoarthritis of knee.

BACKGROUND: Osteoarthritis is one of the most common diseases and the knee is the most commonly affected joint. Intra-articular prolotherapy is being utilized in acute and chronic pain management setting. This study was designed to compare the efficacy of three methods of intra-articular knee joint therapies with erythropoietin, dextrose, and pulsed radiofrequency. MATERIALS AND METHODS: After approval by the Ethics Committee and explaining the therapeutic method to volunteers, 70 patients who were suffering from primary knee osteoarthrosis went through one of the treatment methods (erythropoietin, dextrose, and pulsed radiofrequency). The study was double-blind randomized clinical trial performed from December 2012 to July 2013. Patients' pain level was assessed through the visual analog pain scale (VAS), and range of motion (ROM) was measured by goniometric method. Furthermore, patients' satisfaction was assessed before and after different treatment methods in weeks 2, 4, and 12. For analysis, Chi-square, one-way ANOVA, and repeated measured ANOVA were utilized. RESULTS: The demographic results among the three groups did not indicate any statistical difference. The mean VAS in erythropoietin group in the 2(nd), 4(th), and 12(th) weeks was 3.15 ± 1.08, 3.15 ± 1.08, and 3.5 ± 1.23, respectively (P ≤ 0.005). Knee joint ROM in the erythropoietin group in the 2(nd), 4(th), and 12(th) weeks was 124 ± 1.50, 124 ± 1.4, and 123 ± 1.53 respectively (P ≤ 0.005). Satisfaction score in the 12(th) week in erythropoietin group was extremely satisfied 15%, satisfied 55%, and moderately satisfied 30%, (P = 0.005). No specific side-effects were observed. CONCLUSION: Intra-articular prolotherapy with erythropoietin was more effective in terms of pain level reduction and ROM improvement compared with dextrose and pulsed radiofrequency.

Corrosion response of steels fabricated through arc directed energy deposition additive manufacturing: a review.

Steels exhibit distinct properties that underscore their pivotal role in critical industries, such as maritime, aerospace, automotive, petrochemical, and biomedicine. In recent times, there has been an increasing trend towards manufacturing near-net-shape steel components through various additive manufacturing (AM) modalities, utilizing intricate 3D model data. Initially, powder bed fusion (PBF) technology garnered significant attention for the fabrication of steel components. Nonetheless, arc-directed energy deposition (arc-DED), also known as wire arc additive manufacturing (WAAM) technology, is progressively gaining prominence in the AM enterprise due to its high production rate, the ability to print large-scale components, and notably, reduced capital investment. While early research on WAAM-fabricated steels primarily focused on microstructural and mechanical characteristics, there is an increasing emphasis on the corrosion performance of WAAM steel components. These components often encounter exposure to corrosive environments in their intended applications. The existing literature lacks a comprehensive review that delves into the nuanced factors influencing the corrosion behavior of WAAM-fabricated steels and the primary corrosion mechanisms governing their degradation. Therefore, this review is dedicated to exploring the corrosion properties of WAAM-fabricated steels, identifying key parameters influencing their degradation behavior. Moreover, it offers an in-depth examination and discussion of the underlying mechanisms governing corrosion-induced deterioration. Furthermore, this review meticulously scrutinizes the microstructural features and WAAM technologies, providing clarity and organization regarding details relevant to the corrosion of WAAM steel components. To conclude, the paper highlights the existing research gaps related to the corrosion of WAAM steel, delineating potential avenues for future research.

Effect of Surface Nanocrystallization on Wear Behavior of Steels: A Review.

Ferrous alloys, particularly steels, form a specialized class of metallic materials extensively employed in industrial sectors to combat deterioration and failures caused by wear. Despite their commendable mechanical properties, steels are not immune to wear-induced degradation. In this context, surface nanocrystallization (SNC) technologies have carved a distinct niche for themselves by enabling the nanostructuring of the surface layer (with grain sizes < 100 nm). This process enhances overall mechanical properties to a level desirable for wear resistance while preserving the chemical composition. Existing literature has consistently highlighted the efficacy of various SNC methods in improving the wear resistance of ferrous alloys, positioning SNC as a promising tool to extend materials' service life in practical applications. This review provides a comprehensive examination of the SNC techniques employed in surface treatment of ferrous alloys and their impact on wear behavior. We delved into the underlying mechanisms governing wear in SNC-treated Fe-based alloys and concluded with a discussion on current challenges and future perspectives in this evolving field.

Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions.

Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs) and PlexinD1 located at cell-cell junctions mediates many of these events. But available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn-2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encoding Adgrl2 gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology and disease.

A review of the corrosion behavior of conventional and additively manufactured nickel-aluminum bronze (NAB) alloys: current status and future challenges.

The growing demand for materials with exceptional corrosion resistance and mechanical properties in the aerospace and ocean industries has led to increased research interest in versatile alloys like nickel-aluminum bronze (NAB). NABs exhibit excellent corrosion performance due to the formation of a protective, duplex corrosion product film on the surface, which is largely influenced by their complex microstructure. While NABs are typically produced as cast or wrought products, the emergence of additive manufacturing (AM) technologies has enabled 3D printing of near-net-shape NABs with intricate geometries. This paper provides a critical review of the corrosion properties, passivity, and microstructural characteristics of conventionally produced and AMed NAB alloys, as well as the fundamental mechanisms governing their corrosion behavior under varying conditions. Additionally, it highlights the current research gap and unprecedented challenges associated with the corrosion behavior of traditional and AMed NABs.

MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis.

Insulin activates insulin receptor (IR) signaling and subsequently triggers IR endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis on insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly. Disruption of the IR-MAD2 interaction increases serum fatty acid concentrations and hepatic fat accumulation in fasted male mice. Furthermore, disruption of the IR-MAD2 interaction distinctly changes metabolic and transcriptomic profiles in the liver and adipose tissues. Our findings establish the function of cell division regulators in insulin signaling and provide insights into the metabolic functions of IR endocytosis. ARTICLE HIGHLIGHTS: The physiological role of IR endocytosis in insulin sensitivity remains unclear. Disruption of the IR-MAD2 interaction delays IR endocytosis and prolongs insulin signaling. IR-MAD2 controls insulin clearance and glucose metabolism. IR-MAD2 maintains energy homeostasis.

Genetic evidence of the regulatory role of parathyroid hormone-related protein in articular chondrocyte maintenance in an experimental mouse model.

OBJECTIVE: Parathyroid hormone-related protein (PTHrP) regulates the rate of differentiation of growth chondrocytes and is also expressed in articular chondrocytes. This study tested the hypothesis that PTHrP might have a regulatory role in articular chondrocyte maintenance. METHODS: Control sequences of growth differentiation factor 5 were used to delete PTHrP from articular chondrocytes in the mid-region of mouse articular cartilage. Mice with conditional deletion of PTHrP (knockout [KO]) and littermate control mice were evaluated for degenerative changes using both a time-course design and destabilization of the medial meniscus (DMM) technique. A total histologic score of degenerative changes was determined for the femoral and tibial articular surfaces (total maximum score of 60). RESULTS: The time-course study revealed degenerative changes in only a minority of the KO mice. In the DMM model, male KO mice were highly susceptible to DMM-induced degenerative changes (mean ± SEM total histologic score 45 ± 2.7 in KO mice versus 23 ± 1.4 in controls; P < 0.0001 by Mann-Whitney U test), with virtually no overlap between groups. PTHrP normally functions in a feedback loop with Indian hedgehog (IHH), in which a reduction in one signaling partner induces a compensatory increase in the other. A number of phenotypic and functional markers were documented in KO mice to suggest that the IHH-PTHrP axis is capable of compensating in response to a partial Cre-driven PTHrP deletion, a finding that underscores the need to subject the mouse articular cartilage to a destabilizing challenge in order to elicit frankly degenerative findings. CONCLUSION: PTHrP may regulate articular chondrocyte maintenance in mice.